Project Summary As the population continues to age, cognitive decline and dementia are becoming increasingly important public health issues. Cardiovascular disease and its associated risk factors are related to worse brain health outcomes, including Alzheimer's disease (AD). In particular, central arterial stiffness has been increasingly linked to abnormal cognitive decline in older adults. However, the exact role central arterial stiffness plays in the early development and progression of dementia, such as AD, remains elusive. One purported mechanism underlying associations between age-related arterial stiffness and poor brain health outcomes is increased transmission of harmful pulsatile energy into the distal vasculature. In the brain, these pulsatility changes are associated with microvascular damage that may increase cerebrovascular resistance and decrease vasodilatory reserve. The proposed research will examine relations between age-related aortic stiffening and intracranial vessel morphology, cerebral hemodynamics, and cognition. Primary analyses will utilize innovative, noninvasive imaging techniques to examine relations within a longitudinal, observational cohort of older adults free of clinical dementia and stroke at study entry. Secondary analyses will examine the interaction of aortic stiffening and Apolipoprotein E ?4 allele, a genetic susceptibility risk factor for AD and a well-supported molecular moderator of vascular damage. The proposed research will leverage the rich resources of the Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Institute of Imaging Science, Vanderbilt Advanced Computing Center for Research and Education, Vanderbilt Institute for Clinical & Translational Research, Vanderbilt Translational Clinical Cardiovascular Research Group, and Vanderbilt Brain Institute and include an exceptional mentorship team representing experts in geriatric neuropsychology, AD, cerebrovascular disease, neuroimaging, cardiovascular medicine, human genetics, and biostatistics. The parallel training plan will facilitate the applicant's acquisition of the necessary knowledge and skills to study central vascular health, cerebral hemodynamic factors, and brain aging. The proposed research will elucidate pathophysiological links between age-related aortic stiffening and changes in brain health as well as contributions of macrovascular versus microvascular alterations in aging to cognitive decline over time. Findings will offer a more comprehensive understanding of normal aging and pathological AD profiles for better risk factor identification and pathways for prevention efforts, an especially critical need given the absence of effective AD treatments and the known benefits of early intervention.